Maternal Expression Of MiRNA 379 Cluster Mediates Polar Overdominance Of Callipyge In Mice

Skeletal muscle,one of the three types of muscle tissues,accounts for about forty percent of the human body mass.Skeletal muscle is known to function by maintaining posture,stabilizing bones and joints,controlling internal movement,and participate in thermal homeostasis.In addition,skeletal muscle which is also considered as meat is of economic value.Thus factors promoting efficient early muscle growth is a research focus in livestock industries.Callipyge sheep is an excellent muscular hypertrophy model because they have a profound increase in muscle mass and the callipyge phenotype can be inherited.The callipyge sheep is characterized by superior muscling,high feed efficiency and dressing percentage.All major leg and loin muscles are about 30%heavier in callipyge sheep compared to wild type sheep as a result of a higher percentage and larger average diameter of fast-twitch fibers in the affected muscles.The callipyge mutation was identified as an A-to-G transition which lies within DLK1-DI03 imprinting region.The upregulated DLK1 protein is considered as a very significant role for contributing to callipyge phenopype.On the other hand,the most attention on callipyge phenotype attracting scientific community is its unique non-Mendelian inheritance mode.When the callipyge ram(male)crosses with wild type ewe(female),it yield a 50%to 50%sex independent segregation ratio of the callipyge rams and wild type rams.However,when callipyge ewe(female)crosses with wild type ram(male),it can’t produce callipyge progeny.The second round of cross,mating the callipyge rams and callipyge ewes would not yield 50%callipyge offspring but produce only 25%callipyge rams.It indicate that the callipyge phenotype occurs only when the CLPG allele inherited from the father and wild type allele from the mother(+Mat/CLPG Pat).Most interestingly,the CLPGMat/CLPGPat offspring display wild type phenotype although carrying the CLPG mutation on their paternal chromosome.This non-Mendelian inheritance mode was referred to as polar overdominance.The following researches revealed that the featured expression pattern in normal CLPGPAT/CLPGMAT offspring.The homozygotes offspring express upregulated maternal nocoding RNAs within DLK1-DI03 region accompanied by depressed DLK1 protein,compared to hypertrophied CLPGPAT/+MAT offspring.We proposed the upregulated nocoding RNA act as a trans regulator of DLK1,thus accounting for normal phenotype in CLPG homozygotes.In our studies,ablation of one large microRNA cluster,mir-379-544 cluster,located within DLK1-DI03 region,resulted in hypertrophic and increased masses of tibialis anterior,extensor digitorum longus,gastrocnemius muscle and gluteus maximus muscles along with elevated expression of DLK1 protein in neonatal mice.The featured muscle phenotype was assistant with that in CLPG sheep.Among the microRNAs of the cluster,miRNA-329 inhibited DLK1 expression through targeting 3’ untranslation region.Our observations suggest that polar overdominance inheritance of CLPG is mediated through maternal expression of miRNA379-544 cluster.On the other hand,deletion of this miRNA cluster could also induce soleus muscle atrophy without fiber type switch.The soleus muscle,known as a slow-fiber-dominant muscle,is distinct from other hypertrophied fast muscle.The paradoxical phenotypes in slow muscle indicate miR-379 cluster may act another different role through distinct unidentified pathways.